tbuckley/cabot-search huggingface dataset:
CNSC-04. DIAGNOSIS AND TREATMENT OF PERIPHERAL AND CRANIAL NERVE TUMORS WITH EXPERT RECOMMENDATIONS: AN EUROPEAN NETWORK FOR RARE CANCERS (EURACAN) INITIATIVE
Authors: Alessia Pellerino, Robert M Verdijk, Lucia Nichelli, Nicolaus H Andratschke, Ahmed Idbaih, Roland Goldbrunner
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The 2021 WHO classification of the CNS Tumors identifies as “Peripheral nerve sheath tumors” (PNST) some entities with specific clinical and anatomical characteristics, histological and molecular markers, imaging findings, and aggressiveness. Material and methods. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is particularly low due to the rarity, and drawn recommendations accordingly. RESULTS Tumor diagnosis is primarily based on hematoxylin and eosin-stained sections and immunohistochemistry. Molecular analysis is not essential to establish the histological nature of these tumors, although genetic analyses on DNA extracted from PNST (neurofibromas/schwannomas) is required to diagnose mosaic forms of NF1 and SPS. MRI is the gold-standard to delineate the extension with respect to adjacent structures. Gross-total resection is the first choice, and can be curative in benign lesions; however, the extent of resection must be balanced with preservation of nerve functioning. Radiotherapy can be omitted in benign tumors after complete resection and in NF-related tumors, due to the theoretic risk of secondary malignancies in a tumor-suppressor syndrome. Systemic therapy should be considered in incomplete resected plexiform neurofibromas/MPNSTs. MEK inhibitor selumetinib can be used in NF1 children ≥2 years with inoperable/symptomatic plexiform neurofibromas, while anthracycline-based treatment is the first choice for unresectable/locally advanced/metastatic MPNST. Clinical trials on other MEK1-2 inhibitors alone or in combination with mTOR inhibitors are under investigation in plexiform neurofibromas and MPNST, respectively. CONCLUSIONS Given the heterogeneity and rarity of these tumors, there is a paucity of well-powered clinical trials, thus it is not possible to generate evidence-based treatment recommendations for non-surgical modalities. However, some clinical trials have been reported on targeted therapies in plexiform neurofibromas of NF1 patients or in heterogenous cohorts of soft-tissue tumors, including MPNSTs, with initial data of efficacy that need to be further investigated.
EXTH-01. STEM CELL THERAPY FOR LEPTOMENINGEAL DISEASE
Authors: Yohei Kitamura, Nobuhiko Kanaya, Susana Moleirinho, Ryota Tamura, Ryo Ueda, Hikaru Sasaki, Masahiro Toda, Khalid Shah
Journal: Neuro-Oncology (2023)

Abstract Leptomeningeal disease (LMD), known as carcinomatous meningitis, occurs in approximately 5% of all cancer patients. LMD presents an extremely poor prognosis, with an average life expectancy of 4-6 weeks. Although, whole brain/spinal cord irradiation and intrathecal injection of anticancer drugs are sometimes performed, the effects are limited, so new therapeutic strategies for LMD are urgently needed. We have reported that treatment using engineered stem cells (SCs) may be effective treatment option against LMD of breast cancer, lung cancer, and malignant melanoma, which are types of cancer that tends to metastasize to the central nervous system. Specifically, we reported that engineered allogeneic SCs simultaneously targeting epidermal growth factor receptor (EGFR) and death receptor (DR) has efficacy for LMD of triple negative breast cancer. Also, we reported that twin SCs releasing oncolytic herpes virus, granulocyte-macrophage colony-stimulating factor (GM-CSF), and single-chain variable region fragments (scFv) against PD-1 has efficacy in LMD of malignant melanoma. The greatest advantage of SC based therapeutic strategy for LMD is summarized by these facts: (1) LMD is a condition in which cancer cells spread within a single closed space through cerebrospinal fluid, and the SCs characteristic of homing to tumor cells has an advantage; (2) Repetitive intrathecal injection of drugs for patients is an invasive procedure, but SCs can continuously secrete/release therapeutic agents into the spinal cavity after a single injection. We believe that stem cell therapy has the potential to become a new therapeutic option for LMD in the future.
CSIG-02. SHH PATHWAY ACTIVATION DRIVES NEURAL CREST CELL SIGNATURE IN A SUBGROUP OF MPNSTS
Authors: Suganth Suppiah, Jeffrey Liu, Mira Li, Mohsen Heidari, Rebeca Yakubov, Severa Bunda, Gelareh Zadeh
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Neurofibromatosis Type 1 is hereditary tumor predisposition syndrome that results in the development of innumerable nerve sheath tumors that fall within the spectrum of benign, premalignant and malignant lesions. Our previous work has demonstrated that SHH pathway activation drives malignant transformation in a subset of malignant peripheral nerve sheath tumors (MPNSTs). Here, we demonstrate that SHH pathway activation induces a neural crest cell-like state in a subset of MPNSTs. METHODS We performed single nuclear RNA sequencing on 6 tumors (5 MPNSTS and 1 atypical neurofibroma). We performed in vitro experiments to assess the correlation between SHH pathway activation and neural crest signatures. We inhibited SHH pathway with sonidegib, a SMO inhibitor, in MPNST cell lines and performed RT-PCR to assess markers of neural crest cell signatures. In addition, we assessed cellular viability with treatment. RESULTS We observed that cells that express SMO at high levels, with SHH pathway activation, express neural crest cell makers. Single cell trajectory analysis further demonstrates a pseudotemporal continuum from atypical neurofibromas (Schwann cells), MPNSTs (Schwann cell precursor cells) and other MPNSTs (neural crest cells), which supports that these tumors fall along the developmental trajectory of neural crest cell lineage. SHH pathway activity was high in S462TY MPNST cell line and low in STS-26T MPNST cell line. S462TY also demonstrated prominent elevation in expression of neural crest cell markers TWIST1, SOX9, SNAI2, OTX2, PAX4 and PAX6 . We found that treatment with sonidegib treatment attenuates the expression of neural crest cell signatures. Finally, inhibiting SHH pathway activation reduced cellular viability in MPNST cell lines. CONCLUSION SHH pathway activation drives dedifferentiation into a neural crest cell-like state in a subset of MPNSTs. We confirm that inhibiting SHH pathway activity in a subset of MPNSTS prevent growth and malignant progression, providing a rational for future clinical trials.
DDDR-21. A TEMOZOLOMIDE-INDUCED LONG NONCODING RNA, LINC02454, REGULATES CHEMOSENSITIVITY IN GLIOBLASTOMA VIA MODULATION OF CXCR4
Authors: Edith Yuan, Kathleen Tsung, Jane Han, Wange Lu, Frank Attenello
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Chemoresistance is one of the primary factors influencing the poor prognosis in glioblastoma (GBM) patients. Long noncoding RNAs (lncRNAs) are a novel class of RNAs representing up to 80% of the genome, and noted to induce profound alterations in transcriptional regulation and phenotype, including chemotherapy response. We therefore set out to identify novel lncRNAs induced by chemotherapy that regulate GBM chemosensitivity. We further evaluated the mechanism by which a candidate chemoresistance-associated lncRNA exerts function. METHODS We evaluated gene expression following temozolomide treatment in multiple glioma lines (via RNA-seq). Candidate lncRNAs demonstrating significant expression upon TMZ treatment were assessed for association with patient survival. We further evaluated the effect of knockdown of candidate lncRNAs upon resulting TMZ sensitivity and downstream gene expression. RESULTS Linc02454 was among the most highly upregulated genes following TMZ treatment. Linc02454 resides on chromosome 12q14 within a locus of genes amplified in 10% of GBM patients. Elevated linc02454 expression was associated with decreased survival in TCGA data, while linc02454 knockdown reduced in vitro GBM cell viability in response to TMZ. RNA-seq identified CXC-chemokine receptor 4 (CXCR4) among the most heavily downregulated genes following lncRNA knockdown. Finally, TMZ induces similar increases in linc02454 and CXCR4, while CXCR4 KD chemosensitivity phenotypes closely parallel linc02454 KD phenotypes. CONCLUSION TMZ-induced increases in long noncoding RNAs, particularly in linc02454, regulate expression of well-known and previously targeted chemokines, including CXCR4. Subsequent studies, evaluating the manner by which chemotherapy increases linc02454, and the manner by which linc02454 affects CXCR4 and treatment sensitivity may improve GBM temozolomide sensitivity.
CNSC-30. CD4 T CELLS MEDIATED UPREGULATION OF CCL4 CHEMOKINE DRIVES GLIOBLASTOMA TUMOR MICROENVIRONMENT REPROGRAMMING FOLLOWING TREATMENT WITH A NOVEL MRNA VACCINE
Authors: Anjali Chauhan, Ghaidaa Ebrahim, Farhad Dastmalchi, Kyle McGrath, Nagheme Thomas, Gregory Pal Takacs, Jeffrey Harrison, Matthew Frain, Hector Mendez-Gomez, Elias Sayour, Vignesh Subramaniam, Thomas Angelini, Christina Von Roemeling, Duane Mitchell, Maryam Rahman
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Intra-tumoral immunosuppression is a major cause of treatment failure for patients with glioblastoma (GBM). Our group has developed a proprietary vaccine that combines mRNA encapsulated in lipid nanoparticles with PEG hydrogel and a chemokine (CXCL9). This hydrogel-chemokine-mRNA (HCM) vaccine is delivered subcutaneously (SQ) and results in significant anti-tumor efficacy in syngeneic murine glioma models. The objective of this study was to evaluate the effects of the vaccine on the tumor microenvironment (TME). METHODS C57BL/6 mice underwent intracranial implantation of KR158-luc tumor cells and underwent SQ injection of the HCM vaccine using total tumor mRNA. Tumors were collected for analysis. Q-PCR and flow cytometry were done to evaluate the differential gene expression and CCR5 expression (receptor for CCL4) in the TME. RESULTS CCL4 was found to be upregulated in tumor-bearing animals treated with HCM vaccine using PCR. In a separate experiment, CCL4 blockade was given prior to HCM vaccination and this resulted in abrogation of the survival benefit of the vaccine. Next, flow cytometry was performed and microglia in the TME had the highest expression of the CCR5 receptor. CD4 T cells in the TME had significantly increased CCL4 expression after treatment with HCM vaccine. CONCLUSION The HCM vaccine results in significant anti-tumor efficacy in murine syngeneic murine glioma which is dependent on upregulation of CCL4 in the TME driven by CD4 T cells. The CCL4 exerts its effect through microglia expressing CCR5 in the TME. Further analysis of the effects of vaccination on microglia phenotype and function are underway.
ANGI-09. UNRAVELING THE INVOLVEMENT OF BAIAP2 AND CDC42 IN MEDULLOBLASTOMA PATHOGENESIS
Authors: Luz Ruiz, Nitish Jangde, Robert Suter, Nagi Ayad
Journal: Neuro-Oncology (2023)

Abstract The most common malignant pediatric brain tumor is medulloblastoma. Despite advancements in treatment, medulloblastoma survivors have significant long-term medical side effects and increased all-cause mortality. That is why novel, more effective, and safe treatments are direly necessary. One treatment challenge is that medulloblastoma tumors can disseminate via the bloodstream and cerebrospinal fluid leading to a poorer prognosis. The underlying mechanisms that promote metastasis and invasion in medulloblastoma are not clearly understood. One method we used to identify potential key regulators in the pathogenesis of medulloblastoma is by analyzing microarray and single-cell RNA sequencing data. We mined publicly-available datasets along with our data from genetically engineered models of medulloblastoma to identify differentially expressed genes compared to non-tumor brain cells. We identified BAIAP2 and CDC42 to be differentially expressed and have higher expression in medulloblastoma compared to other brain cancers. BAIAP2 and CDC42 are known to be implicated in migration and invasion. Extensive literature demonstrates an interaction between BAIAP2 and CDC42 in multiple cell types. However, this interaction has yet to be thoroughly studied in medulloblastoma. We hypothesize that CDC42 interacts with BAIAP2 in medulloblastoma cells to facilitate tumor pathogenesis. To further investigate this, we conducted siRNA-mediated gene knockdown of BAIAP2 and CDC42 in ONS-76 cells. We determined that BAIAP2 and CDC42 are highly expressed in medulloblastoma, and knockdown of BAIAP2 modulates CDC42 expression. Further, we determined that cell proliferation and migration were reduced upon BAIAP2 and CDC42 knockdown. Our findings suggest that BAIAP2 and CDC42 have a role in the migration and proliferation of medulloblastoma ONS-76 cells. Altogether, these findings indicate BAIAP2 and CDC42 as possible targets for future studies.
CTNI-37. CLINICAL ACTIVITY OF RAF INHIBITOR TOVORAFENIB ACCORDING TO PRIOR MAPK INHIBITOR TREATMENT IN THE REGISTRATIONAL PEDIATRIC LOW-GRADE GLIOMA ARM OF THE PHASE 2 FIREFLY-1 (PNOC026) STUDY
Authors: Dong-Anh Khuong-Quang, Karsten Nysom, Daniel Landi, David Ziegler, Pablo Hernáiz Driever, Sarah Leary, Simon Bailey, Jasper van der Lugt, Sébastien Perreault, Angela Waanders, Patricia Baxter, Olaf Witt, Darren Hargrave, Geoffrey McCowage, Jordan Hansford, Helen Toledano, Liat Oren, Enrica E K Tan, Nicolas Gerber, Hyoung Jin Kang, Valérie Larouche, Mohamed S Abdelbaki, Izzy Cornelio, Yeonhee Kim, Ashley Walter, Peter Manley, Lindsay Kilburn
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor. Genomic alterations of RAF are common oncogenic drivers in pLGG. Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor. METHODS FIREFLY-1 (NCT04775485) is a phase 2 study evaluating tovorafenib monotherapy. Registrational arm 1 enrolled patients aged 6 months–25 years of age with recurrent or progressive LGG harboring an activating BRAF alteration. Tovorafenib 420 mg/m2 (600 mg max) was administered weekly (tablet or liquid suspension). Independently assessed overall response rate (ORR), as defined by RANO-HGG and RANO-LGG criteria, are primary and exploratory endpoints. RESULTS As of December 22 2022, 69 (RANO-HGG) and 76 (RANO-LGG) of 77 patients in arm 1 were evaluable at baseline and had ≥9 months of follow-up. Median age at enrollment was 8 years (range 2–21), and 60% (n = 46) patients had received prior MAPK inhibitor (MAPKi) therapy. Among the evaluable patients, the ORR was 62% (RANO-HGG, n = 69) and 45% (RANO-LGG, n = 76), respectively. The ORR in patients previously treated with MAPKis (n = 41 [RANO-HGG]; n = 45 [RANO-LGG]) was 68% (4 CRs; 24 PRs) (RANO-HGG) and 44% (5 PRs; 15 MRs) (RANO-LGG). In MAPKi-naïve patients (28 [RANO-HGG]; 31 [RANO-LGG]), the ORR was 54% (15 PRs) (RANO-HGG) and 45% (7 PRs; 7 MRs) (RANO-LGG). Among 136 patients in arms 1 and 2 of FIREFLY-1, the most common treatment-related adverse events (TRAEs) of any grade were hair color changes (71%), fatigue (40%) and maculopapular rash (38%). Tovorafenib dose modifications occurred in 39 (29%) and discontinuations in 4 (3%) patients due to TRAEs. CONCLUSIONS Tovorafenib provided clinically meaningful tumor responses, including those with a best response reported of SD or PD using another MAPKi, in patients with BRAF-altered pLGG regardless of prior MAPKi therapy, and has a manageable safety profile.
INNV-22. TEMOZOLOMIDE DESENSITIZATION AND CONSIDERATIONS FOR IMPLEMENTATION IN AN ACADEMIC MEDICAL CENTER: A CASE REPORT
Authors: Jenna Wojkowski, Aphrodite Palazis, Princess Ogbogu, Kathryn Ruda Wessell, Patricia Roberts, Herbert Newton
Journal: Neuro-Oncology (2023)

Abstract Temozolomide is an alkylating agent commonly used in the treatment of central nervous system (CNS) malignancies, including glioblastoma multiforme (GBM). Rashes have been noted to occur in about 19% of patients receiving temozolomide, with severe rashes ( &amp;gt; grade 3) only noted in about 1% of patients. Here we report the case of a 42-year-old female patient diagnosed with GBM who presented with widespread, progressive urticaria on her chest, abdomen, back, legs, and arms during her first adjuvant cycle of temozolomide. With temozolomide being a standard of care in the treatment of GBM, our team decided to attempt a second adjuvant cycle via desensitization prior to exploring alternative treatment options. There is currently no standard for temozolomide desensitization; however, there are a few published case reports. Based on existing literature, a protocol was developed and utilized for a total of four additional cycles. During the second, third, and fourth desensitization cycles, which were completed in the outpatient setting, the patient experienced headache, urticaria, and nausea/vomiting. A steroid taper was prescribed and the patient completed the desensitization protocol and the remainder of each of the aforementioned cycles without further issues. Our case report provides a review of the current literature and discusses operational considerations and limitations related to temozolomide desensitization protocol development and execution. This case illustrates the need for additional data to determine efficacy of desensitization compared to standard dosing regimens.
STEM-06. OSMR INTERACTOME MAPPING REVEALS THE SIGNIFICANCE OF A CHLORIDE CHANNEL IN CYTOKINE REGULATION AND BRAIN TUMOUR STEM CELL SELF-RENEWAL
Authors: Kamaldeep Randhawa, Laura Raco, Jamie Snider, Igor Stagljar, Arezu Jahani-Asl
Journal: Neuro-Oncology (2023)

Abstract Oncostatin M Receptor (OSMR) is a key regulator of brain tumour stem cell (BTSC) self-renewal and glioblastoma (GB) tumourigenesis. This receptor is found in a complex with Epidermal Growth Factor Receptor variant III (EGFRvIII) and orchestrates a positive feedback loop with STAT3. OSMR also regulates oxidative phosphorylation and participates in promoting the transition of cells towards mesenchymal-like glioma states. How OSMR drives GB tumorigenesis via multiple mechanisms remains largely unclear. Here, we map OSMR interactome in different GB subtypes using the Mammalian Membrane Two Hybrid High Throughput Screen (MaMTH-HTS). Analysis of these data followed by functional validation has uncovered distinct OSMR interactome in a context dependent manner. Follow up investigations, however, have led to the discovery of the Chloride Intracellular Channel 1 (CLIC1), essential in the regulation of OSMR cytokine signaling and GB progression independently of the genetic profile of the GB tumour. CLIC1 forms a complex with OSMR to promote BTSC self-renewal and knockout of CLIC1 or pharmacological inhibitors to CLIC1 impairs OSM mediated STAT3 phosphorylation. Our work suggests that CLIC1 and OSMR form a complex in BTSCs and functionally interact to activate STAT3.
CTIM-07. PHASE IIB RANDOMIZED, BLINDED, CONTROLLED TRIAL EVALUATING NEOADJUVANT PD-1 BLOCKADE COMBINED WITH A2B5+ GLIOMA STEM-LIKE CELL LYSATE-LOADED DCV IN RECURRENT GLIOBLASTOMA (IDH1/2 -)- TRAIL IN PROGRESS
Authors: Yu Yao, Xiaoming Huang, Di Chen, Lang Hu, Bingyi Zhou, Chenwei Li, Lingchao Chen, Nan Zhou, Chunxia Ji, Yuan Wang, Liangfu Zhou
Journal: Neuro-Oncology (2023)

Abstract Our previous phase II randomized trials have determined that A2B5+ glioma stem-like cell lysate-loaded DC vaccine (GSC-DCV) demonstrates favorable safety and significantly extends the survival of glioblastoma (GBM) (NCT01567202). This study aims to investigate the clinical feasibility and efficacy of the GSC-DCV combined with aPD-1 mAbs neoadjuvant therapy in recurrent GBM (NCT04888611). GBM (IDH1/2 -) patients who had received radiotherapy and TMZ chemotherapy were enrolled in the study after pathologically confirmed recurrence. All patients received aPD-1 mAbs treatment (3mg/kg, up to 200mg) 14±5 days before surgery. Following surgery, eligible patients were randomized in a 1:1 ratio to receive either a combination treatment of aPD-1 mAbs with GSC-DCV or aPD-1 mAbs with placebo. The above-mentioned postoperative therapy was given every three weeks until disease progression or unacceptable toxicity. Besides evaluating treatment response using the iRANO criteria, MRI scans were conducted before each treatment and after surgery (in 72h) to evaluate tumor size/volume to analyze the relationship between tumor burden and prognosis. The primary endpoint of the study was overall survival, while the secondary endpoints included the evaluation of treatment-related adverse events (trAEs) and the measurement of indicators related to the immune response. From October 2021 through May 2023, a total of 22 patients were enrolled and successfully randomized. At the latest follow-up, the two groups were generally balanced with respect to baseline characteristics, encompassing age, gender, KPS, steroid use, MGMTp status, TERTp status, and tumor volume at registration. Notably, differences in survival were observed between the two groups, with respective follow-up periods ranging from 1.3 to 19.9 months and 1.0 to 12.1 months. The incidence of trAEs in all patients was 22.7%, with no grade 3 or higher trAEs observed thus far, and the main adverse event was reactive cutaneous capillary endothelial proliferation (RCCEP).
CTNI-32. IMPLEMENTING GENOMIC PROFILING AS STANDARD-OF-CARE FOR GLIOBLASTOMA PATIENTS
Authors: Vincent Fougner, Thomas Urup, Benedikte Hasselbalch, Hans Poulsen, Kristoffer Rohrberg, Iben Spanggard, Martin Højgaard, Laila Belcaid, Christina Yde, Ulrik Lassen, Dorte Noeroexe
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The introduction of targeted therapies (TT) has provided few new options for glioblastoma patients (pts). Implementing genomic profiling as standard-of-care may aid in finding new treatments for glioblastoma pts. Here, we report the impact of genomic profiling in pts with WHO grade 4 CNS tumors at the Department of Oncology, Rigshospitalet, Denmark. METHODS Eligible pts were ≥18 years of age, with newly diagnosed glioblastoma; astrocytoma, IDH mutated grade IV or diffuse midline glioma between January 2016 and December 2022. Whole exome sequencing (WES), whole genome sequencing (WGS) or panel sequencing with Trusight Oncology (TSO500) along with SNP-array analyses and RNAseq was performed on DNA/RNA extracted from tumor tissue. Tumor tissue from patients enrolled before 2021 were analyzed by WES, and from January 2021 and forth, WGS was used for frozen tissue and TSO500 for paraffin-embedded tissue. Each genomic profile was presented at a weekly national molecular tumor board meeting for multidisciplinary evaluation, treatment recommendations and matching with clinical trials. RESULTS 387 pts had tissue samples available for analysis. Tissue from 202 patients (52%) were analyzed using WES, 174 (45%) using WGS, and 11 (3%) using TSO500. As of May 2023, of the 343 sequenced pts that have progressed after standard therapy, 14 patients (4%) have been treated with molecularly matched TTs. The actionable targets were TMB-high ( &amp;gt;10mut/MB) (n = 4), FGFR-mutations/-fusions (n = 4), BRAFv600E (n = 2), NTRK-fusions (n = 2), PDGFRA-fusion (n = 1) and MET-mutation (n = 1). Additionally, germline mutations were reported in 8 patients (2%). CONCLUSION Genomic profiling revealed actionable targets and new therapeutic options for glioblastoma pts. A full and updated overview of patient characteristics, actionable targets and survival data will be presented at the meeting.